Systems and methods for neuromodulation for treatment of pain and other disorders associated with nerve conduction

ABSTRACT

Methods and apparatus are provided for selective destruction or temporary disruption of nerves and/or conduction pathways in a mammalian body for the treatment of pain and other disorders. Apparatus comprises catheters having electrodes for targeting and affecting nerve tissue at a cellular level to reversible and irreversible nerve poration and incapacitation.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/459,582, filed on Jul. 24, 2006 (Attorney Docket No.020979-003510US), which claims the benefit of Provisional ApplicationNo. 60/701,747, filed Jul. 22, 2005 (Attorney Docket No.020979-003500US), the full disclosures of which are incorporated hereinby reference.

BACKGROUND 1. Field of the Invention

The present invention relates to methods and apparatus for the treatmentof nerve function, and more particularly, for selective disruption ofconduction pathways in the body for the treatment of pain and otherdisorders associated with nerve conduction in various regions within thebody.

Approximately 50 million Americans suffer with persistent (chronic)pain. The number of people suffering with chronic pain is higher thanthe number suffering from serious or terminal illnesses. Yet, unlikemajor illnesses, most chronic pain is untreated or under-treated. Painsurveys report that 42% of those experiencing chronic pain have suchsevere pain that they are unable to work, and 63% of pain sufferers areunable to engage in the routine activities of daily life. It has beenestimated that among active workers, the loss of productivity fromcommon pain syndromes costs over 60 billion dollars annually. In recentyears, consumer advocacy, demographics, and advances in pain controltechnology have highlighted the clinical need for solutions and advancedthe practice of pain management to a priority for healthcare providers.

Irreversible surgical ablation has been relied upon for the treatment ofchronic pain. Lesions are placed on or in the peripheral nerves, spinalchord or brain, but such placement can have side effects such asunintended motor system effects, and required open, surgical procedures.More recently, reversible electrical and localized pharmacologicsolutions started to be used.

Electrical techniques, such as neurostimulation, which deliver a lowvoltage electrical stimulation to a targeted peripheral nerve or spinalchord to essentially block the sensation of pain as recognized by thebrain. First used in the 1960's, electrical stimulation of theperipheral nerves was shown to mask pain with a tingling sensation(paresthesia). This mechanism is part of the “gate control theory ofpain” (Melzack and Wall, Science (1965) 150: 971-979.), proposing that a“gate” exists in the spinal chord that controls the transmission of painsignals to the brain. The theory suggests that activation of certainnerve fibers in the dorsal horn of the spinal chord can “close the gate”thereby inhibiting or muting the pain signals.

A variety of different electrical stimulation techniques have beenemployed to achieve such blocking of the pain signals, includingTranscutaneous Electrical Nerve Stimulation (TENS) which providesnon-invasive (skin surface) electrical stimulation to the largemylenated fiber spinal afferents, which functionally blocks nerve signaltransmission to essentially create a “short circuit” between the nervefibers and the sensory pathway to the brain. TENS may be applied toperipheral nerve stimulation, as well as spinal chord stimulationutilizing electrodes placed at the site of the targeted nerve.

In addition, a technique utilizing stronger electrical stimulationapplied to acupuncture needles placed beneath the skin, referred to asElectroacupuncture or Acupuncture Like Transcutaneous Nerve Stimulation(ALTENS), has been employed with the goal of optimizing the release ofendorphins and serotonin to combat pain. Various electrical stimulationdevices are described in U.S. Pat. Nos. 4,573,481, 3,911,930 and4,141,365, each of which is hereby incorporated by reference in theirentirety.

The LISS Cranial Stimulator (LCS) and the LISS Body Stimulator (LBS)which deliver a monopolar current at a frequency of 15,000 Hz, modulatedat 50 ms “on” and 16.7 ms “off” has been used for pain treatment. (Liss,et al., (1996) Behavioral Science 31: 88-94) U.S. Pat. Nos. 5,983,141and 6,246,912 to Sluijter describe the application of an electromagneticsignal to neural tissue for pain relief through an electrode to alterthe function of the tissue without causing temperatures that are lethalto the tissue.

Stimulation of the sensory thalamus and periaqueductal orperiventricular gray in the deep brain has also shown promise intreating patients that have not been helped by other less invasivemodalities of treatment. In this approach, electrodes are placed in thetargeted regions of the brain under stereotactic guidance. Stimulationis then applied and when a satisfactory results is achieved, a signalgenerator may be implanted for long term use. A variety of severe sideeffects can result from this approach however, including intracerebralhemorrhage and life threatening infections.

Another approach used widely is orally administered opiates andnarcotics, however the systemic effect and addictive nature of the oralmedications make them less likely to provide a long term solution.Localized drug delivery or intraspinal drug administration has alsoshown promise, due to the fact that the approach requires significantlylower doses of narcotics that are delivered directly to the targetedregion of the spinal chord either through epidural or intrathecaladministration. In these approaches, percutanous catheters may be placedat the target region, and attached to implantable (subcutaneous)reservoirs or pumps, or external drug pumps. Even though the narcoticsare localized, side effects may still present, including impairment ofmotor function, nausea, constipation, ulcers and other side effectsattendant oral narcotic administration.

Various technologies are currently marketed to treat pain and othermotor dysfunctions. Advanced Neuromodulation Systems (Plano, Tex.)manufactures an RF transmitter and probe for spinal chord stimulation aswell as an implantable drug delivery system to relieve chronic pain, thelatter being described in U.S. Pat. No. 5,938,690, hereby incorporatedby reference in its entirety. Vertis Neuroscience (Vancouver, Wash.)provides externally placed, targeted electrode arrays that providestimulation to the upper and lower back to provide relief to chronicpain referred to as Percutaneous Neuromodulation Therapy (PNT™).Synaptic Corporation (Aurora, Colo.) provides a product for externalstimulation for chronic pain by creating electrical impulses alongspecific sensory nerve pathways to inhibit pain signals to the brain,effect tissue healing, and produce general tissue anesthesia, as furtherdepicted in U.S. Pat. No. 6,161,044, hereby incorporated by reference inits entirety. US2004/0186532 describes an electrode implantable in thebrain stem to deliver electrical stimulation to treat pain.

Additional implantable systems include, a rechargeable spinal chordstimulation system that includes an implantable pulse generator andleads attached to various regions of the spine that are connected to anexternal remote control or alternative charging system. Such systems areavailable from Advanced Bionics, a division of Boston Scientific,Natick, Mass. and from Medtronic, Inc. Minneapolis, Minn. Such systemsare described in U.S. Pat. No. 6,847,849. The Medtronic system may alsoinclude drug delivery technology including intrathecal drug delivery.

Although promising, many of these systems do not provide a lastingeffect, and for some, the therapeutic effect is only felt while thetherapy is being administered. The treatment of intractable chronic painremains a challenge.

In light of the foregoing, it would be desirable to provide methods andapparatus for treating pain and other disorders associated with nerveconductivity within the human body. The methods and apparatus preferablyare minimally invasive or non-invasive, are targeted to specific tissue,such as nerve tissue, and provide a long therapeutic effect. It wouldfurther be desirable to provide devices and methods that modify nervefunction without necessarily causing permanent physical nerve damage(neuralgia) that can occur once the treated nerve regenerates. At leastsome of these objectives will be met by the inventions described below.

All publications and patents or patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent or patent application wasspecifically and individually so incorporated by reference.

BRIEF SUMMARY

The following presents a simplified summary of some embodiments of theinvention in order to provide a basic understanding of the invention.This summary is not an extensive overview of the invention. It is notintended to identify key/critical elements of the invention or todelineate the scope of the invention. Its sole purpose is to presentsome embodiments of the invention in a simplified form as a prelude tothe more detailed description that is presented later.

The present invention provides methods and apparatus for treating painand other nerve related disorders where the methods and apparatus areminimally or non-invasive, controlled and selective, and/or offer a moredurable effect.

Methods and apparatus according to the present invention treat chronicpain and other neural defects by delivering energy to disrupt nervetissue at the cellular level to cause permeabolization (poration) of thecell membrane to affect the viability of the nerves at the targetedregion. Target nerves include nerves in the spine, particularlycervical, thoracic, lumbar and sacral regions of the spine; peripheralnerves; nerves of the head and neck; and the brain stem. Depending onthe amplitude and duration of the applied field, the “poration” of thetarget nerve may be reversible or irreversible, as desired. Reversibleelectroporation may be used in conjunction with a nerve blocking agent,chemical or other therapeutic agent to enhance, modify or otherwisemodulate disruption of the nerves and/or targeted tissue.

In one aspect of the present invention methods and apparatus areprovided for treating chronic pain and other neural defects bydelivering an electric, ultrasonic or other energy field generated by apulse or pulses of a designated duration and amplitude to disrupt nerveor other tissue at the cellular level via permeabolization of the cellor cell membrane.

In a further aspect of the invention, the energy may be delivered underconditions selected to cause irreversible cell damage by the creation ofpores in the cell membrane which result in the death of the cell.Alternatively, the conditions may be selected to cause reversible orpartially reversible cell damage.

In another aspect of the invention, intracellular electromanipulation ofthe targeted tissue (such as nerve tissue) using ultrashort electricfield pulses leading to apoptosis of the targeted cell may be desirable.

A further aspect of the invention is to provide methods and apparatusfor treating chronic pain and other neural defects by utilizing anelectric field to disrupt tissue at the cellular level viapermeabolization of the cell causing reversible electroporation of thecellular membrane, preferably by delivering an electric pulse or chainof pulses having a voltage between 40V and 1,000,000V. Such reversibleelectroporation may be applied in conjunction with a therapeutic agentsuch as a nerve blocking agent, a neurotoxin or neurotoxin fragment,such as the light chain portion of botulinim toxin serotype A.

In a further aspect of the invention, it may be desirable to providemethods and devices that selectively disrupt certain cell types and notothers, to provide a therapy that can be applied from multiple locationswithin the body.

In a preferred aspect of the present invention, the target nerves arefrequently located adjacent to arteries which can be used forpercutaneous access to the nerves. for example, vascular cathetershaving electrodes, ultrasonic transducers, or other energy sources attheir distal ends may be advanced through an artery to an arterial siteadjacent to the target nerve which often runs directly along the outsideof the artery. energy can be applied which denervates the nerve whileleaving the arterial wall intact as the nerve cells are more susceptibleto injury. Thus, a single treatment can damage the adjacent nerve forextended periods of months or more without damaging the artery used foraccess.

Examples of arteries that can be used to access particular target nervesof the body regions include:

Artery Nerve Carotid Cranio-facial Vertebral Cranio-facial RadialPeripheral (Arms and Hands) Femoral Lower limbs, Sciatica, Disc PainPopliteal Lower limbs, Sciatica, Disc Pain

In a specific aspect of the present invention, patients suffering fromrefactory angina may be treated by reversible or irreversible disruptionof the stellate ganglion in the neck in the area of the C6 vertebra(FIG. 1B) and/or of the paravertebral nerves in the spine in the area ofthe T6 vertebra (FIG. 1B). The stellate ganglion and associated nervescan be treated or denervated by passing a nerve poration catheter intothe common, internal or external arteries, placing the treatmentelectrode(s) or other component adjacent the nerve level to be treated,and delivering energy to cause irreversible poration to the targetnerves. Some nerves may be better accessed via catheter placement in thevertebral or subclavian arteries. Nerves in the area of T6 can beaccessed by placing the treatment catheter in the aorta, anterior orposterior spinal arteries, radicular arteries, intercostal arteries, ormedullary arteries.

The examples of arteries accessed and nerves treated to address variouspain syndromes should be considered exemplary in nature and notlimiting. It should be recognized that any syndrome which is amenable bytreatment by denervation will be amenable to treatment via by theinventive technology.

For a fuller understanding of the nature and advantages of the presentinvention, reference should be made to the ensuing detailed descriptionand accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the invention, its nature and various advantageswill be more apparent from the accompanying drawings and the followingdetailed description, in which:

FIG. 1A—depicts a Dermatome showing areas of the body (skin) supplied bycorresponding nerve fibers on front of body;

FIG. 1B—depicts a Dermatome showing areas of the body (skin) supplied bycorresponding nerve fibers on rear of body;

FIG. 2—depicts a side view of three vertebrae in a vertebral columnshowing certain relationships between spinal nerve roots and vertebrae;

FIG. 3—depicts a schematic of spinal nerve and vertebrae.

FIG. 4—depicts a generator and catheter system capable of supply pulsedelectric fields to effect reversible or irreversible electroporation intargeted cells.

FIGS. 4A and 4B—depict catheter distal tips of the present invention invarious configurations showing spaced apart electrodes, including anoptional monitoring electrode.

FIGS. 5A-D—depict various electrode catheter configurations adapted todeliver energy or energy and therapeutic agents to target tissue.

FIG. 6—depicts a fully implantable pulse generator and lead of thepresent invention.

FIG. 7—depicts an implantable receiver and external transmitter andcontroller for delivering energy according to the present invention.

FIG. 8—depicts a schematic representing placement of the implantableversion of the present invention.

FIGS. 9A and B—depict an electrode pad for placement on the skin of apatient, including one or multiple circuits, either smooth orincorporating microneedles.

FIG. 10—depicts a method of use of the invention according to FIGS. 9Aand 9B.

FIG. 11—depicts a method of use of the invention according to FIG. 6.

FIG. 12—depicts a method of use of the invention according to FIGS.5A-5D.

FIG. 13—depicts a method of use of the invention according to FIG. 7.

FIG. 14—depicts a schematic of a nerve fiber showing the relative cellsize allowing selective cell permeabolization of nerve cells.

FIG. 15—depicts a schematic of a target nerve region being treated by aporation catheter in an adjacent artery.

DETAILED DESCRIPTION

In the following description, various embodiments of the presentinvention will be described. For purposes of explanation, specificconfigurations and details are set forth in order to provide a thoroughunderstanding of the embodiments. However, it will also be apparent toone skilled in the art that the present invention may be practicedwithout the specific details. Furthermore, well-known features may beomitted or simplified in order not to obscure the embodiment beingdescribed.

The present invention is directed to methods and apparatus fortargeting, stimulating, and disrupting nerve tissue, or tissue adjacentnerve tissue (collectively “target tissue”) usually at the cellularlevel, in order to selectively denervate or disrupt nerves and nervepathways responsible for creating a pain response in a mammalian body.Target tissue may be treated from one or more locations either adjacentto or at a distance from target tissue. The target tissue may includethe nerve directly associated with the pain response and/or conductionpathways contributing directly or indirectly to the pain response.

Pain syndromes that may be treated utilizing the present inventioninclude, neuropathic and nociceptive pain, for example, musculoskeletalpain (back, neck shoulder), myofascial (muscle) pain, neuropathic pain(complex regional pain syndrome, central pain syndrome, neuralgia,neuropathy), headaches, cancer pain, fibromyalgia, pelvic pain,arachnoiditis, arthritis, facial pain (TMJ, Temporomandibular disorders(TMD)), sciatica, skin disorders (burn pain, shingles, herpes, tumors,vasculitis), spacicity, spinal chord injury or stenosis, sickle celldisease, and pain associated with vascular disease, both peripheral andcardiac.

The body's nervous system consists of the central nervous system(brain), spinal chord nerves and the peripheral nervous system (sensorynerve fibers and motor nerve fibers outside of the brain and spinalchord). The system includes nerves (bundles of axons enclosed inconnective tissue) and can be characterized as sensory/afferent,motor/efferent, or a combination of both sensory and motor fibers. Thespinal nerves include fused nerve roots, for example, the dorsal rootnerves are associated with sensory functions, and the ventral rootnerves are associated with motor functions. Peripheral nerves may becranial (arising from the brain), or spinal (arising from the spinalcolumn), and are usually associated with sensations or motor functionsin the hands, arms, legs or feet.

Cranial nerves are mostly associated with motor function, or acombination of motor and sensory functions. As shown in FIG. 2, thespinal nerves consist of 31 pairs of nerves organized into variousregions along the spine the cervical (C), thoracic (T), lumbar (L), andsacral (S). The spinal nerves are further organized into nerve networksor nerve plexus including C1-C4 (cervical plexus), C5-C8 and T1(brachial plexus), L1-14 (lumbar plexus), and L4-S4 (sacral plexus). Therelationship between the spinal nerve and the muscle (myotome) andbetween spinal nerve and skin (dermatome) are depicted in FIGS. 1A and1B, showing the nerves associated with the particular region of thebody. In treating pain or other disorders associated with nerveconduction in the body, devices can target a relatively localized regionof the spinal column depending on the type of pain or motor function andlocation of pain or motor function (dermatome or myotome) to be treated.

Devices of the present invention may be directed to “targeted regions”such as cervical, thoracic, lumbar and sacral regions of the spine,peripheral nerves, nerves of the head and neck, brain stem, and deepbrain. Some particular examples include, spinal chord modulation forchronic pain (for example application of energy of the present inventionto the region of the spine at L1-L5 to treat lower limb and/or backpain), peripheral nerve modulation for chronic pain (for example theradial or ulnar nerve to treat hand or finger pain or dysesthesias.),and sacral nerve modulation to treat pelvic pain. In some instances, thedevices and methods of the present invention may also be employed totreat certain motor dysfunctions; for example, spinal chord nervemodulation to treat peripheral vascular disease (PVD), deep brain nervemodulation for tremor, Parkinsons, depression, obsessive compulsivedisorder, motor dysfunction, and brain injury, and vagus nervemodulation for treatment of epilepsy, or obesity.

High Voltage Pulsed Electric Fields. To achieve the goals of the presentinvention, it may be desirable to employ methods and apparatus forachieving nerve modulation and/or denervation utilizing pulsed electricfields and/or electroporation applied directly to the targeted region orin proximity to the targeted region to produce the desired denervationor nerve disruption. For purposes of this disclosure, the term“electroporation” can encompass the use of pulsed electric fields(PEFs), nanosecond pulsed electric fields (nsPEFs), ionophoreseis,electrophoresis, electropermeabilization, sonoporation and/orcombinations thereof, permanent or temporary, reversible orirreversible, with or without the use of adjuctive agents, withoutnecessitating the presence of a thermal effect. Similarly, the term“electrode” used herein, encompasses the use of various types of energyproducing devices, including antennas (microwave transmitters) andultrasonic elements. In practice, sonoporation, cell membranemanipulation by application of ultrasonic energy, may have advantages inperforming the therapeutic treatment of the present invention due to itsability to manipulate the membrane without producing as much heat at thetreatment site as other energy modalities that have been used, and itsability to focus at a specific treatment site.

The methods and apparatus of the present invention can employ reversibleelectroporation of the type used in medicine and biology to transferchemicals, drugs, genes and other molecules into targeted cells for avariety of purposes such as electrochemotherapy, gene transfer,transdermal drug delivery, vaccines, and the like. Irreversibleelectroporation may also be employed as used for cell separation indebacterilization of water and food, stem cell enrichment and cancercell purging (U.S. Pat. No. 6,043,066 to Mangano), directed ablation ofneoplastic prostate tissues (US2003/0060856 to Chomenky), treatment ofrestenosis in body vessels (US2001/0044596 to Jaafar), selectiveirreversible electroporation of fat cells (US 2004/0019371 to Jaafar)and ablation of tumors (Davalos, et al. Annals of Biomedical Engineering33: 223-321. The entire contents of each of these references areexpressly incorporated herein by reference.

Energy fields applied in ultrashort pulses, or nanosecond pulsedelectric fields (nsPEFs) may also be used to porate target nerve andother cells in accordance with the present invention. Ultrashort pulselengths are directed at target subcellular structures withoutpermanently disrupting the outer membrane. An example of this technologyis described by Schoenbach et al. (2001) J. Bioelectromagnetics 22:440-448, and in U.S. Pat. No. 6,326,177, the contents of which isexpressly herein incorporated by reference. The short pulses target theintracellular apparatus, and although the cell membrane may exhibit anelectroporative effect, such effect is reversible and does not lead topermanent membrane disruption. Following application of nanosecondpulses, apoptosis is induced in the intracellular contents, affectingthe cell's viability (for example limiting the ability to reproduce).

In a specific embodiment of the present invention, electroporation maybe achieved by energizing an electrode or series of electrodes toproduce an electric field. Such a field can be generated in a bipolar ormonopolar electrode configuration. When applied to cells, depending onthe duration and strength of the applied pulses, this field operates toincrease the permeabolization of the cell membrane and either (1)reversibly open the cell membrane for a short period of time by causingpores to form in the cell lipid bilayer allowing entry of varioustherapeutic elements or molecules, after which, when energy applicationceases, the pores spontaneously close without killing the cell, or (2)irreversibly opening or porating the cell membrane causing cellinstability resulting in cell death utilizing higher intensity (longeror higher energy) pulses, or (3) applying energy in nanosecond pulsesresulting in disruption of the intracellular matrix leading to apoptosisand cell death, without causing irreversible poration of the cellularmembrane. As characterized by Weaver (1993), Journal of CellularBiochemistry 51: 426-435, short (1-100 μs) and longer (1-10 ms) pulseshave induced electroporation in a variety of cell types. In a singlecell model, most cells will exhibit electroporation in the range of1-1.5 V applied across the cell (membrane potential).

Certain factors determine how a delivered electric field will affect atargeted cell, including cell size, cell shape, cell orientation withrespect to the applied electric field, cell temperature, distancebetween cells (cell-cell separation), cell type, tissue heterogeneity,properties of the cellular membrane and the like. Larger cells may bemore vulnerable to injury. For example, skeletal muscle cells have beenshown to be more susceptible to electrical injury than nearby connectivetissue cells (Gaylor et al. (1988) J. Theor. Biol. 133: 223-237). Inaddition, how cells are oriented within the applied field can make themmore susceptible to injury, for example, when the major axis ofnonspherical cells is oriented along the electric field, it is moresusceptible to rupture (Lee et al. (1987) Plastic and ReconstructiveSurgery 80: 672-679.)

Various waveforms or shapes of pulses may be applied to achieveelectroporation, including sinusoidal AC pulses, DC pulses, square wavepulses, exponentially decaying waveforms or other pulse shapes such ascombined AC/DC pulses, or DC shifted RF signals such as those describedin Chang, (1989) Biophysical Journal October 56: 641-652, depending onthe pulse generator used or the effect desired. The parameters ofapplied energy may be varied, including all or some of the following:waveform shape, amplitude, pulse duration, interval between pulses,number of pulses, combination of waveforms and the like.

Catheter Devices. FIGS. 4 and 4A-4B depict a system 10 comprising anelectroporation catheter 12 for selective denervation/disruption ofnerve tissue. For purposes of this specification, the term “catheter”may be used to refer to an elongate element, hollow or solid, flexibleor rigid and capable of percutaneous introduction to a body (either byitself, or through a separately created incision or puncture), such as asheath, a trocar, a needle, a lead. In certain configurations of thepresent invention, voltages may be applied via the electroporationcatheter 12 to induce irreversible electroporation, without requiringthe use of any other agents to achieve the desired cell destructionand/or denervation. It is a further advantage of this type of energythat any thermal effect may be minimized thereby preventing orminimizing collateral damage to tissues near the target tissues, or thetype of physical damage to the nerves themselves that can lead topermanent neuralgia when the nerve fibers generate A further advantageof this type of energy is that the electroporation orelectropermeabilization effect is largely cell-size specific. That is,larger cells will be porated (either reversibly or irreversibly) atlower energy levels than smaller cells. This will allow the denervationeffect to be directed at the relatively large nerve cells while sparingsmaller adjacent cell types. In addition, the electric field may becontrolled by the size and relative positioning of the electrodes on thetreatment device or patient.

The electroporation catheter system 10 further comprises a pulsegenerator 14 such as those generators available from Cytopulse Sciences,Inc. (Columbia, Md.); Bio-Rad, Inc. (Hercules, Calif.) (the Gene PulserXcell); and IGEA (Carpi, Italy). The pulse generator is electricallyconnected to the catheter 12 which has a proximal end 20 and a distalend 22 and is adapted for either surface placement (cutaneous) orminimally invasive insertion into the desired region of the body asdescribed herein. The generator 14 may be modified to produce a highervoltage, increased pulse capacity or other modifications to induceirreversible electroporation. The catheter 12 further comprises anelectroporation element at the distal end thereof comprising a firstelectrode 30 and a second axially spaced-apart electrode 32 operativelyconnected to the pulse generator through cables 34 for delivering thedesired number, duration, amplitude and frequency of pulses to affectthe targeted nerve tissue. The energy delivery parameters can bemodified either by the system or the user, depending on the location ofthe catheter within the body (e.g., the nature of the interveningtissues or structures) and whether a reversible or irreversible cellporation is desired. For example energy in the range of 10 V/cm to 10⁴V/cm for a duration of 10 μs to 100 ms may be used to achieve reversibleelectroporation and in the range of 100 V/cm to 10⁶ V/cm for a durationof 10 μsec to 100 msec to achieve irreversible electroporation orapoptosis. As shown in FIG. 4A, electrodes 30 and 32 may be axiallyaligned on one side of catheter 12 to produce an electric fieldconcentrated in a lateral direction from the catheter body. Using ringelectrodes 30 and 32 as shown in FIG. 4B, creates a more uniformelectric field about the shaft of the catheter 12. Additional monitoringelectrode(s), may be located on the catheter 12.

Further catheter devices and electrode configurations are shown in FIGS.5A-5D. FIG. 5A depicts an elongate catheter 50 having a first electrode52 and second electrode 54 near its distal tip. A monitoring orstimulation electrode 56 is disposed in the vicinity of the poratingelectrodes 52 and 54 for monitoring or localizing the treatment area. Insome embodiments, the monitoring or stimulating function may beperformed by one or more of the treatment electrodes. The catheter 50may have an optional sharp tip 58 (shown in broken line) to facilitatepercutaneous introduction. Electrodes 52, 54 and 56 are shown as axiallyaligned on one side of the catheter 50 but could also have ring or otherstructures.

FIG. 5B illustrates a steerable catheter 60 adapted to bend orarticulate at a region 62 near its distal end. Active electrodes 64 and66 are disposed adjacent to or within the articulated region 62 and amonitoring or stimulation electrode 68 is optionally disposed proximallyof the active electrodes. Such steering ability enables the operator tointroduce the device into tight or tortuous spaces so that optimalplacement of the device may be achieved.

FIG. 5C depicts a catheter 70 that includes an injection element 72 toallow for the injection of a therapeutic agent before, during or afterthe application of the pulsed energy or electroporation from activeelectrodes 74 and 76 and monitoring or stimulating electrode 78. Theinjection element may be a needle as shown in FIG. 5C, an infusion port,or other infusion means. Such a therapeutic agent may be, for example,lidocaine, botulinum toxin (either full or in fragment as detailedcopending application Ser. No. 11/459,090 (Attorney Docket No.020979-003410US, filed on Jul. 21, 2006, the full disclosure of whichhas been incorporated herein by reference), capsaicin or a variety ofnerve blocking agents. The use of the devices and methods of the presentinvention can increase the effectivity and provide for alternative meansof delivery for botulinum toxin to treat pain by inhibiting the releaseof the neurotransmitter responsible for the transmission of pain, suchas various neuropathic diseases and disorders as described in U.S. Pat.Nos. 6,113,915, 6,333,037, 6,372,226, 6,841,156, 6,896,886 and 6,869,610to Aoki, the contents of which are expressly incorporated herein byreference in their entirety. Further, to aid the electroporationprocess, it may be advantageous to heat the targeted cells orsurrounding tissue by either applying thermal energy directly to theregion, or directing a heated fluid, such as saline to the regionthrough the injection element.

FIG. 5D depicts a catheter 80 having deployable electrode elements 82and 84 that are adapted to extend laterally from the main catheter body,and in some cases, penetrate the surrounding tissue prior to applicationof energy. In doing so the depth and direction of the energy fieldcreated by the electroporative process, may be further controlled. Aswith the previous embodiments, a stimulating or monitoring electrode 86may optionally be provided proximally of the active electrodes.

In certain configurations it may be advantageous to use the porationcatheters and methods of the present invention in conjunction with anerve blocking agent, neurotoxin, neurotoxin fragment or othertherapeutic agents according to methods and devices described inco-pending patent application Ser. No. 11/459,090 (Attorney Docket No.020979-003410US), filed on Jul. 21, 2006, the full disclosure of whichhas been incorporated by reference in its entirety. In this instance,the voltage applied to the electrode elements would preferably be in therange applicable to create a reversible electroporation of the nerve ortissue cells, thereby porating the cell to allowing the therapeuticagent to be delivered to achieve the desired effect, but not destroyingthe cell or otherwise irreversibly damaging the targeted tissue or nervestructures.

Any of the foregoing systems may include electrodes or other monitoringsystems either located on the treatment catheter, or external to thepatient, to determine the degree of treatment to the region, including,thermocouple, ultrasound transducers, fiberoptics, sensing orstimulating electrodes. Further, it may be desirable to incorporatemultiple pairs of electrodes that may be activated in pairs, in groups,or in a sequential manner in order to maximize the desired shape of thelesion while minimizing the field strength requirements. Also, thedevices of the present invention may be used in conjunction with moretraditional neuromodulation techniques, such as TENS, to mediate painattributable to the treatment (the presence of which may depend on thelevel of voltage applied) or neuromuscular response to the appliedelectric field as further noted in published U.S. Application No.2003/0149451, hereby incorporated by reference in its entirety.

Implantable Devices. A fully implantable spinal cord modulation system100 includes an implantable pulse generator 102 which incorporates apower supply or battery as depicted in FIG. 6. The system 100 connectsto an implantable lead 104 which includes electrodes 106 and 108. Asshown in FIG. 7, a partially implantable system 120 includes atransmitter 122, and a receiver 124 that relies upon radio frequency totransmit the energy to the lead or electrode. In this system the antennaand transmitter are carried outside the body, while the receiverconnected to the lead 126 with electrodes 128 and 130) is implantedinside the body. FIG. 8 shows the placement of the fully implantablepulse generator 100 device in the region of the sacral plexus of apatient which has been implanted according to the steps set forth inU.S. Pat. No. 6,847,849, previously incorporated by reference herein.Implantation of the partially implantable system 120 could be achievedin the identical manner.

Cutaneous or Subcutaneous Devices. For some conditions, it may bedesirable to apply the poration energy from the surface of the skin(transcutaneously), or from just below the skin (subcutaneously). FIG.9A depicts a dermal patch 150 having an electrode pair 152 and 154 fordelivery of therapeutic energy of the present invention to the targetedregion. Alternatively, the pad may include one electrode, while theother (a ground) may be positioned elsewhere on the patient's skin (notshown). Depending on the type of voltage applied and condition to betreated, it may be desirable to have multiple electrode pairs on thesurface of the patch or pad, and in some cases as shown in FIG. 9B, suchelectrodes may be in the form of microneedles 160 that puncture the skinsome distance to deliver the therapeutic energy of the present inventionsubcutaneously. The patch or pad carrying the electrodes should beflexible and conformable and may be formed of a polymer such assilicone, urethane, nylon, polyethylene or other thermoplasticelastomers, or could be substantially rigid and formed of a rigidpolymer (such as PEEK or polysulfone) or insulated stainless steel,nickel titanium alloy, or other metal. As noted above, variousmonitoring devices and methods may be employed to track the progress ofthe therapy. Similarly, algorithms to activate pairs of electrodes orregions of the pad or patch may be employed to enhance the therapeuticeffect while reducing the overall power requirements.

Intraluminal Devices. It may further be advantageous to positionporation catheters through vessels in the body, particularly arteries totreat adjacent nerves, to direct poration energy to various regions toeffect pain reduction. Such intraluminal catheters are described inpublished U.S. Applications 2001/0044596 to Jaafar and 2002/0198512 toSeward, hereby incorporated by reference in their entirety, could beused for such energy delivery.

Methods of Use. FIG. 10 illustrates a method for nerve poration byapplying energy to the surface of the skin S via the electrode patch150. FIG. 11 depicts the implantation of electrode lead 104 or 126 thatis then operatively connected to the implantable generator and describedherein. FIG. 12 shows percutaneous nerve poration catheter 12 implantedin a region within the spine. In FIGS. 11 and 12, the active tip regionof the catheter or lead is shown placed alongside the nerve region NR tobe treated, but in fact may be positioned within the nerve sheath, oralong the spine (SP), or within the muscular layer (MP).

In yet another embodiment shown in FIG. 13, a receiver 200 may be placedat the target location (here alongside the nerve region NR in the spineSP), while a transmitter 202 is placed outside or on the skin of thepatient. Once in place adjacent the nerve region NR to be treated, apulse generator in the transmitter 202 may be activated, causing anelectric field to be generated in the target area. Prior to activationof therapeutic voltages, once the catheter(s) have been appropriatelypositioned, stimulation using one or more electrodes may be used toelicit a nerve response. By observing the nerve reflex, a targettreatment location can be confirmed, and then application of porationenergy is employed to eliminate or disrupt the nerve and associated painresponse, thereby selectively denervating the conduction pathways forthe particular type of pain to be treated.

In operation, effects of poration on nerve tissue may be selective dueto the cellular structure and orientation of the nerve cells. Forexample as shown in FIG. 14, targeted nerve cells may be preferentiallyaffected due to size, sparing smaller or cross-oriented muscle tissue.As shown, the energy may selectively rupture the nerve cells 220 at ends222 while the energy dissipates over the main body of the cells.

As shown in FIG. 15, poration catheter 12 can be introduced into a lumenof artery A to a location immediately adjacent to a nerve region NR tobe treated. The catheter 12 will typically be introduced over aguidewire GW under fluoroscopic guidance using well-known intravascularintervention methods and protocols. Once in place, electroporation orother poration energy can be applied across the arterial wall toward thenerve region NR to denervate the nerve as described previously. As thenerve cells will typically be more susceptible to energy induced damage,the desired temporary or permanent denervation can usually be achievedwith minimum or no damage to the artery. The catheter 12 can be removedafter the treatment session is completed. The treatment can be repeatedmonths or years later if and when nerve function returns.

Although various illustrative embodiments of the present invention aredescribed above, it will be evident to one skilled in the art thatvarious changes and modifications may be made without departing from thescope of the invention. It will also be apparent that various changesand modifications may be made herein without departing from theinvention. The appended claims are intended to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

Other variations are within the spirit of the present invention. Thus,while the invention is susceptible to various modifications andalternative constructions, certain illustrated embodiments thereof areshown in the drawings and have been described above in detail. It shouldbe understood, however, that there is no intention to limit theinvention to the specific form or forms disclosed, but on the contrary,the intention is to cover all modifications, alternative constructions,and equivalents falling within the spirit and scope of the invention, asdefined in the appended claims.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. The term “connected” is to beconstrued as partly or wholly contained within, attached to, or joinedtogether, even if there is something intervening. Recitation of rangesof values herein are merely intended to serve as a shorthand method ofreferring individually to each separate value falling within the range,unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein, is intended merely to betterilluminate embodiments of the invention and does not pose a limitationon the scope of the invention unless otherwise claimed. No language inthe specification should be construed as indicating any non-claimedelement as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

1. An apparatus for selective denervation of a target tissue in apatient's body, the target tissue comprising nerve cells, the apparatuscomprising: a non-implantable intraluminal catheter adapted to bepercutaneously introduced into a lumen of an artery, the catheter havingone or more electrodes disposed thereon, wherein said electrode(s) areadapted to transmit at least one of an electrical pulse or a series ofelectrical pulses; and a pulse generator operatively connected to thecatheter, wherein the electrodes and generator are configured to delivercellular poration energy in the range from 10 V/cm to 10⁶ V/cm to nervecells outside the lumen of the artery to disrupt a pain conductionpathway by inducing apoptosis of the nerve cells, wherein the pulsegenerator is electrically connected to a proximal end of theintraluminal catheter outside the patient's body to deliver cellularporation energy to the one or more electrodes when the catheter ispercutaneously introduced into the lumen of the artery.
 2. The apparatusof claim 1, wherein the catheter is adapted to be positionedpercutaneously in an artery to position said electrode(s) at a locationadjacent to a region of a spine in a human patient selected from thegroup consisting of a cervical region, a thoracic region, a sacralregion and a lumbar region.
 3. The apparatus of claim 1, wherein thecatheter is adapted to be positioned percutaneously in an artery toposition said electrode(s) at a region of peripheral nerves in a humanpatient.
 4. The apparatus of claim 1, wherein the pulse generator andelectrodes are adapted to deliver poration energy at from 10 V/cm to 10⁴V/cm for durations from 10 μsec to 100 msec to achieve reversibleporation.
 5. The apparatus of claim 1, wherein the pulse generator andelectrodes are adapted to deliver poration energy at from 100 V/cm to10⁶ V/cm for durations from 10 μsec to 100 msec to achieve irreversibleporation.
 6. An apparatus for selective denervation of a target tissue,the target tissue comprising nerve cells having membranes, the apparatuscomprising: an electrode support having one or more electrodes disposedthereon, wherein said electrode(s) are adapted to transmit at least oneof an electrical pulse or a series of electrical pulses; and a pulsegenerator operatively connected to the electrode support, wherein theelectrodes and generator are configured to deliver cellular porationenergy in the range from 10 V/cm to 10⁶ V/cm for durations from 10 μsecto 100 msec to disrupt a pain conduction pathway by disruptingtarget-tissue nerve-cell membranes, wherein the support comprises apatch and the one or more electrodes are configured on the patch to beapplied to a skin.
 7. The apparatus of claim 6, wherein the one or moreelectrodes comprise one or more micro needles.
 8. A method for selectivedenervation of a targeted tissue of a patient, said method comprisingdelivering energy to target nerve cells of said target tissue underconditions selected to disrupt a pain conduction pathway-bypermeabilizing a cell membrane of said target nerve cells.
 9. A methodas in claim 8, wherein the target cells are nerve cells.
 10. A method asin claim 9, wherein the nerve cells are selected from the groupconsisting of nerves of a spine, peripheral nerves, nerves of a head andneck, and a brain stem.
 11. A method as in claim 10, wherein the nervecells are in the spine.
 12. A method as in claim 11, wherein the targetspinal nerve cells are in a region of a sacral plexus.
 13. A method asin claim 11, wherein the target spinal nerve cells comprise those in astellate ganglion in the region of C6.
 14. A method as in claim 10,wherein the target spinal nerve cells are in an area of T6.
 15. A methodas in claim 9, wherein the nerve cells are outside a lumen of an arteryand the energy is delivered from within the lumen of the artery.
 16. Amethod as in claim 15, wherein said energy is delivered from a cathetertransluminally positioned in the artery.
 17. A method as in claim 8,wherein the energy is electric delivered in the range from 10 V/cm to10⁶ V/cm for a period in the range from 10 μsec to 100 msec.
 18. Amethod as in claim 8, wherein the energy is delivered under conditionswhich provide a reversible poration.
 19. A method as in claim 18,wherein the energy is electrical in the range from 10 V/cm to 10⁴ V/cm.20. A method as in claim 8, wherein the energy is delivered underconditions which provide an irreversible poration.